Halogenated Pyrrolopyrimidines with Low MIC on Staphylococcus aureus and Synergistic Effects with an Antimicrobial Peptide
Abstract
:1. Introduction
2. Results
2.1. Study Design
2.2. Synthesis of Fused Pyrimidines
2.3. Evaluation of Antibiotic Activity
2.3.1. Variation of the 4-Amino Group
2.3.2. Variation of the 6-Aryl Group and the 7-Heteroatom
2.3.3. Combination Studies with the Antimicrobial Peptide Betatide
2.3.4. Structure-Activity Relationship
2.4. Kinase Off-Targets and Mechanistic Studies
3. Experimental Section
3.1. Chemicals and Materials
3.2. Analysis and Characterization
3.3. Synthetic Protocols
3.3.1. Amination of Fused Pyrimidines (General Procedure A)
3.3.2. Regioselective Suzuki Cross-Coupling (General Procedure B)
3.3.3. SEM-Deprotection (General Procedure C)
3.4. Preparation of Compounds 1–21
3.4.1. (R)-4-(4-((1-Phenylethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (1)
3.4.2. (R)-4-(4-((1-(p-Tolyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (2)
3.4.3. (R)-4-(4-((1-(4-Chlorophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (4)
3.4.4. (R)-4-(4-((1-(4-Bromophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (5) from 28
3.4.5. (R)-4-(4-((1-(4-Bromophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (5) from 35
3.4.6. (R)-4-(4-((1-(4-Iodophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (6)
3.4.7. (R)-4-(4-((1-(3-Bromophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (7)
3.4.8. 4-(4-((4-Bromobenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (8)
3.4.9. (S)-4-(4-((1-(4-Bromophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (9)
3.4.10. (R)-4-(4-((1-(4-Bromophenyl)ethyl)(methyl)amino)-7H-pyrrolo [2,3-d]pyrimidin-6-yl)phenol (10)
3.4.11. (S)-N-(1-(4-Bromophenyl)ethyl)-6-(4-methoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (11)
3.4.12. (R)-N-(1-(4-Bromophenyl)ethyl)-6-phenyl-7H-pyrrolo[2,3-d] pyrimidin-4-amine (12)
3.4.13. (R)-N-(1-(4-Bromophenyl)ethyl)-6-(4-fluorophenyl)-7H-pyrrolo[2,3-d] pyrimidin-4-amine (13)
3.4.14. (R)-N-(1-(4-Bromophenyl)ethyl)-6-(4-nitrophenyl)-7H-pyrrolo [2,3-d] pyrimidin-4-amine (14)
3.4.15. (R)-6-(4-Aminophenyl)-N-(1-(4-bromophenyl)ethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (15)
3.4.16. Methyl (R)-4-(4-((1-(4-bromophenyl)ethyl)amino)-7H-pyrrolo[2,3-d] pyrimidin-6-yl)be-nzoate (16)
3.4.17. (R)-4-(4-((1-(4-Bromophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)benzene-sulfonamide (17)
3.4.18. (R)-2-(4-((1-(4-Bromophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (18)
3.4.19. (R)-3-(4-((1-(4-Bromophenyl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)phenol (19)
3.4.20. (R)-N-(1-(4-Bromophenyl)ethyl)-6-(4-methoxyphenyl)thieno [2,3-d] pyrimidin-4-amine (20)
3.4.21. (R)-4-(4-((1-(4-Bromophenyl)ethyl)amino)thieno[2,3-d]pyrimidin-6-yl)phenol (21)
3.5. Bioassays
3.5.1. MIC Measurements
3.5.2. E. coli and Human TMPK Assay
3.5.3. In Vitro EGFR (ErbB1) Inhibitory Potency
3.5.4. Kinase Panel
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Comp. | | E. coli MIC [mg/L] 1 | S. aureus MIC [mg/L] 1 | Human EGFR [%] 2 |
---|---|---|---|---|
1 | | >128 | 64 | 100 |
2 | | >128 | 16 | 91 |
3 | | >128 | >128 | 92 |
4 | | >128 | 16 | 91 |
5 | | >128 | 8 | 81 |
6 | | >128 | 8 | 43 |
7 | | >128 | 16 | 89 |
8 | | >128 | >128 | 67 |
9 | | >128 | >128 | ND 3 |
10 | | >128 | >128 | 16 |
| |||||
Comp. | 6-Aryl | X | E. coli MIC [mg/L] 1 | S. aureus MIC [mg/L] 1 | Human EGFR[% Inhibition] 2 |
11 | | NH | >128 | >128 | - |
12 | | NH | >128 | >128 | 66 |
13 | | NH | >128 | >128 | 58 |
14 | | NH | >128 | >128 | 33 |
15 | | NH | >128 | >128 | 90 |
16 | | NH | >128 | >128 | 42 |
17 | | NH | >128 | >128 | 85 |
18 | | NH | >128 | >128 | 80 |
19 | | NH | >128 | 16 | 73 |
20 | | S | >128 | >128 | 12 |
21 | | S | >128 | 32 | 5 |
| ||||
Comp. | 4-Amino Group | Scaffold | Single Comp. MIC [mg/L] | Combination with Betatide MIC [mg/L] |
1 | | A | 64 | 8 |
2 | | A | 16 | 8 |
4 | | A | 16 | 4 |
5 | | A | 8 | 1 |
6 | | A | 8 | 2 |
7 | | A | 16 | 4 |
19 | | B | 8 | 2 |
21 | | C | 32 | 4 |
Betatide | - | 16 |
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Olsen, C.E.; Blindheim, F.H.; Søgaard, C.K.; Røst, L.M.; Singleton, A.H.; Bergum, O.E.T.; Bruheim, P.; Otterlei, M.; Sundby, E.; Hoff, B.H. Halogenated Pyrrolopyrimidines with Low MIC on Staphylococcus aureus and Synergistic Effects with an Antimicrobial Peptide. Antibiotics 2022, 11, 984. https://doi.org/10.3390/antibiotics11080984
Olsen CE, Blindheim FH, Søgaard CK, Røst LM, Singleton AH, Bergum OET, Bruheim P, Otterlei M, Sundby E, Hoff BH. Halogenated Pyrrolopyrimidines with Low MIC on Staphylococcus aureus and Synergistic Effects with an Antimicrobial Peptide. Antibiotics. 2022; 11(8):984. https://doi.org/10.3390/antibiotics11080984
Chicago/Turabian StyleOlsen, Cecilie Elisabeth, Fredrik Heen Blindheim, Caroline Krogh Søgaard, Lisa Marie Røst, Amanda Holstad Singleton, Olaug Elisabeth Torheim Bergum, Per Bruheim, Marit Otterlei, Eirik Sundby, and Bård Helge Hoff. 2022. "Halogenated Pyrrolopyrimidines with Low MIC on Staphylococcus aureus and Synergistic Effects with an Antimicrobial Peptide" Antibiotics 11, no. 8: 984. https://doi.org/10.3390/antibiotics11080984